Engineered TCRs Targeting Mutated RAC1 and RAC2 Neoepitopes
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Solution Overview
Problem
Current adoptive T-cell therapies targeting cancer-specific antigens often result in on-target off-tumor toxicity and limited efficacy, particularly in treating cancers associated with mutated Rho GTPases like RAC1 and RAC2, which are involved in various human diseases including cancers, due to the specificity and cross-reactivity of existing T-cell receptors.
Innovation Solution
Development of novel antigen binding proteins (ABPs) and genetic constructs that specifically recognize mutated RAC1 and RAC2 peptides presented by MHC molecules, such as RAC2P29L and RAC1P29S, allowing for targeted immune responses with reduced off-target binding, using recombinant host cells and nucleic acid constructs to produce these ABPs for therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing T-cell receptors are used to target cancer-specific antigens, then immune response is activated, but on-target off-tumor toxicity occurs and efficacy is limited
Solution Approach 1:
The patent applies local quality by engineering T-cell receptors with modified complementarity determining regions (CDRs) that are specifically optimized to recognize unique neoepitopes derived from mutated RAC1 and RAC2 proteins. This localized modification of the TCR binding interface enables high-specificity recognition of cancer cell neoepitopes while avoiding cross-reactivity with normal tissues, thereby resolving the contradiction between therapeutic efficacy and toxicity.
Solution Approach 2:
The patent employs parameter changes by systematically modifying amino acid sequences in the TCR CDR regions to alter binding affinity and specificity parameters. Through rational design and screening of TCR variants with different binding characteristics, the invention achieves optimal balance between strong recognition of cancer neoepitopes and minimal off-target binding, thus improving efficacy while reducing toxicity.
2Measurement precision
If T-cell receptors with high specificity for mutated RAC1 and RAC2 are developed, then therapeutic precision is improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the TCR molecule into distinct functional modules: variable regions (Vα and Vβ) containing complementarity determining regions (CDRs 1-3) for antigen recognition, and constant regions for structural support and signaling. This modular organization allows independent optimization of binding specificity in the CDR segments while maintaining overall TCR structure, thereby achieving high precision without excessive complexity.
Solution Approach 2:
The patent utilizes universality by designing TCRs that recognize a panel of related neoepitopes from both RAC1 and RAC2 mutations using a common structural framework. The engineered TCRs can bind to multiple neoepitope variants through conserved binding interfaces, providing broad cancer coverage with a single TCR design approach, thus improving precision while controlling complexity.
Data Source
AI summary
The invention is based on antigen binding proteins (ABPs) such as T-cell receptors (TCR) expressed on T-cells, which have a specificity to bind to MIC presented Rac2 and Rac1 derived neo-epitopes. Hence, such MHC presented peptides are derived from mutated versions of Rac1 and Rac2, such as preferably RAC2P29L and/or RAC1P29S. Provided are isolated ABPs as well as genetic constructs expressing the ABPs, recombinant host cells harboring the ABP of the invention and methods for producing such ABPs and host cells. Moreover, provided are medical applications involving the TCR of the invention, for example in context of an adoptive T-cell therapy.